Obesity and metabolic dysfunction often lead to systemic inflammation, immune suppression and insulin resistance which increases fasting insulin levels. Insulin is a potent stimulator of cancer growth but is rarely measured when assessing cancer prognosis and progression. That has important implications for cancer patients, as hyperinsulinemia (high fasting insulin) as well as hyperleptinemia (high leptin — another fat hormone and common in obesity) are closely associated with cancer progression and mortality.
Traditionally, few cancer researchers have included metabolic biomarkers in their clinical studies or as endpoints. Research has recently discovered that obesity interferes with many cancer treatments, including immunotherapy. With the science behind metabo-oncology revealing the profound impact obesity and metabolic dysfunction have on cancer patients’ treatments and outcomes, that situation is likely to change.
There is very good evidence that deregulated insulin signaling, which is a feature of pre-diabetes, is associated with certain types of cancer. It’s also very clear that elevated fasting insulin levels are associated with an increased risk of breast cancer as well as a worse prognosis.
Kathy Pan (Los Angeles Biomedical Research Institute) led a study on insulin resistance in postmenopausal women. The study showed that women in the top quartile of the HOMA-IR [homeostasis model assessment of insulin resistance] were at significantly increased risk of both all-cause mortality and cancer-specific mortality. Extrapolating these results to the general population would mean 8-10 million American women are at increased risk [of cancer-specific mortality due to insulin resistance].
Many cancer researchers study activating mutations in the PI3-kinase (PI3K) pathway, since they are significantly implicated in a lot of different types of tumors. But there are other ways this pathway can be triggered. For instance, insulin can activate the PI3K pathway. This means that the actual availability of growth factors that are circulating might have mitogenic effects in obese cancer patients, even if their tumors don’t have PI3K pathway mutations. We need to keep this in mind so that patients are not misclassified.
Published data from our groups and other groups has shown that the standard metabolic markers, like insulin, glucose and the adipokines, become altered in a subclinical way during initial cancer treatment, which doesn’t set off any red flags in the clinic. But they do become altered during subsequent chemotherapy. And those patients who’ve had alterations in those markers are at a higher risk of going on to develop frank metabolic disorders, like diabetes or hypertension.
While the tumor-centric approach — where cancer prevention and cancer treatments are directed at the biology of the tumor itself — has been successful, we’re learning we can enhance this success by also focusing on the person as a whole and on what’s going on around the tumor. This is where metabo-oncology really becomes important, because the metabolic state of a person as a whole contributes quite a bit to how tumors develop and behave.
In my practice, which primarily treats women with breast cancer, we follow glucose all the time. The other thing is abnormal liver function tests. If the patient has had abnormal liver function tests, then we’ll get a liver ultrasound and usually diagnose steatosis. Fat infiltration of the liver is a marker of the metabolic syndrome, and it’s dangerous for these ladies.
Oncology treatments have not evolved over the past 70 years; they’ve been incredibly cancer cell-centric. Tumor cells do not exist in a vacuum. The host that surrounds or encapsulates those tumor cells has a tremendous influence on the ability of those cells to propagate, divide and metastasize. In oncology, we just continue to treat the tumor cell. We don’t treat the host for risk factors at all.
In my research, we’ve seen that some of the inflammatory effects arising in adipose tissue can cause myeloid cell infiltration into the lung parenchyma, which creates a nurturing environment for breast cancer metastasis to grow. We found that elevated interleukin-5 or GM-CSF within the blood are triggering events for lung neutrophilia and metastasis. But our research also suggests that this process is reversible with weight loss. This opens up possibilities for lifestyle interventions in patients.
As you gain weight, adipocytes become hypertrophic and sometimes die. Adipocyte death triggers phagocytes, like macrophages, to be recruited to clean up the cellular debris. This stimulates damage recognition pathways that are integral to basic immunology, by upregulating cytokines that are needed to mount an immune response. Cytokines can communicate systemically to other immune cells, to activate T cells and trigger adaptive immune responses. They’re highly conserved defense mechanisms. They’ve evolved to protect our bodies, but unfortunately these same mechanisms are now chronically hijacked during obesity and instead have detrimental effects.
We know that exercise has an amazing effect on the immune system.
At the very core of our physiology is this genome that’s very adaptive to environmental stresses in the form of physical activity and caloric restriction. And what we have in today’s society is a mismatch where we over-stress the system in terms of overconsumption and over-nutrition, and under-stress it in terms of physical activity — but our genome hasn’t changed. So we’ve got a fundamental mismatch between the environment and our genome. I think cancer is accelerated as a result of that mismatch.
The research on physical activity and insulin is really outstanding. The effects that it has are; a) an alteration in the upregulation of the glut4 transporter that helps the insulin get [glucose] inside cells, i.e. improved insulin sensitivity, and b) upregulation of the movement of the glut4 transporters to the cell wall.
Strength training has a long-term effect, at least for as long as you keep the added muscle mass. It’s a pretty simple concept: You increase muscle mass, so there is more muscle mass into which you can put your glucose and improve insulin sensitivity.
Now that’s just one outcome. We could also talk about the difference between what you would do for bone health in a survivor of breast, gynecologic or prostate cancer — diagnoses associated with poor bone health. The answer is that you have to do enough to load the bone. There has to be a high enough load of the bone and a progression of loading of the bone.
Kerri Winters-Stone at Oregon Health & Science University has shown that if you get people with prostate cancer to do progressive resistance training twice a week, starting low and slowly increasing the weight and the number of sets and reps over time, then you get a nice effect [on strength].
Those who have excess adiposity are frequently both metabolically deregulated and inflamed. In fact, the two are likely interrelated; having inflamed fat undoubtedly contributes to metabolic deregulation. Some have also suggested that type II diabetes is an independent prognostic factor for cancer.
What has happened with immunotherapy over the past few years is more of an appreciation of the role that the tumor microenvironment can have. But it’s been very much within that context of tumor cells and the immediate surrounding microenvironment. What we haven’t appreciated is the role of the host in influencing tissue landscapes as well as microenvironments of normal tissue and those that contain or harbor tumor cells.
People who are interested in the microenvironment — and really think that the microenvironment is a necessary contributing factor to tumor progression — understand the importance of metabo-oncology. They understand that incorporation and consideration of adipocytes, adipocyte dysregulation and metabolic syndrome are all contributing factors to cancer, and that the genetic drivers of a tumor aren’t the sole determinants of outcome.
This is about building an evidence base. It’s not just one study that’s going to be the smoking gun. We’re going to need an accumulation of convincing evidence to make change here. I think we have enough of a foundation to move forward, but we’ve still got a lot of work to do.